Neurological conditions are disorders of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, lack of coordination, loss of sensation, as well as pain. Interventions include preventative measures, lifestyle changes, physiotherapy or other therapy, neuro-rehabilitation, pain management, medication, or operations performed by neurosurgeons (WHO Neurological Disorders: Public Health Challenges, 2006). These conditions or disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause. The broadest division is between central nervous system (CNS) disorders and peripheral nervous system (PNS) disorders (Merck Manual: Brain, Spinal Cord and Nerve Disorders, 2010-2011).
Traumatic injury to the adult central nervous system (CNS) is associated with multiple different types of damage, all of which pose substantial challenges to attempts to achieve tissue repair. Restoration of neurological function after severe injury requires regenerative growth of severed motor and sensory axons through the provision of growth factors, appropriate substrates and/or overriding of a variety of inhibitors that prevent axon regeneration.
Currently there is an acute clinical demand for novel therapies that promote robust levels of functional recovery when administered to the traumatically injured or diseased central nervous system (CNS). Scar tissue that forms after traumatic injury to the adult mammalian CNS is rich in axon growth inhibitory chondroitin sulfate proteoglycans (CSPGs) and inhibitory to axon growth (Davies, S. J., et al. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680-683 (1997); Davies, S. J. et al., Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord J. Neurosci 19, 5810-5822 (1999)). Misaligned fibrotic scar tissue in large CNS injuries clearly presents a physical barrier to axon growth, however failure of axon regeneration can even occur within minimal injuries in which tissue alignment is rapidly restored (Davies S. J., et al. Regeneration of cut axons fails even in the presence of continuous aligned glial pathways. Exp. Neurol. 142; 203-216 (1996)), highlighting a molecular inhibition of axon growth within CNS injuries. Several individual CSPGs, such as neurocan, NG2, brevican and phosphacan, have been shown to be inhibitory to axon growth in vitro and are up-regulated at sites of adult CNS injury (reviewed in Morgenstern D. A., et al., Chondroitin sulphate proteoglycans in the CNS injury response. Prog. Brain Res 137, 163-173 (2002)). Other axon growth inhibitors such semaphorin 3A have also been shown to be upregulated within scar tissue at sites of brain and spinal cord injury (Pasterkamp R. J. et al. Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS, Mol. Cell Neurosci 13: 143-166 (1999); Pasterkamp R. J. et al. Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin3A, Eur. J. Neurosci. 13: 457-471 (2001); Pasterkamp R. J. and. Kolodkin A. L, Semaphorin junction: making tracks toward neural connectivity, Curr. Opin. Neurobiol. 13:79-89 (2003)). In addition to upregulation of inhibitory CSPGs within scar tissue that forms directly at sites of injury, inhibitory CSPGs and semaphorin 3A are also known to be present at high levels with normal spinal cord gray matter and after CNS injury (Pasterkamp R. J. et al. Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS, Mol. Cell Neurosci 13: 143-166 (1999); Pasterkamp R. J. and. Kolodkin A. L, Semaphorin junction: making tracks toward neural connectivity, Curr. Opin. Neurobiol. 13:79-89 (2003); Andrews E. M. et al. Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury, Exp. Neurol. ePub ahead of print (2011); Tang X., et al. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue, J. Neurosci. Res. 71: 427-444 (2003). Furthermore, it has been shown that myelin sheaths around axons with adult CNS white matter also presents a variety of axon growth inhibitory molecules such as NOGO (Neurite outgrowth inhibitor), myelin associated glycoprotein (MAG) and oligodendrocyte myeilin glycoprotein (OMgp: reviewed in Yiu G. and He Z. Glial inhibition of CNS axon regeneration, Nat. Rev. Neurosci. 7: 617-627 (2006).). Thus severed axons attempting to regenerate across sites of injury, then through myelin rich white matter beyond injury sites and finally extending axonal “collateral” side branches from white matter into gray matter (in order to establish functional synaptic connections), must navigate through different domains of the injured CNS that contain multiple axon growth inhibitory molecules.
Small leucine rich proteoglycans (SLRP) of the extracellular matrix (EM) comprise an expanding family of proteoglycans and glycoproteins that now encompass five distinct groups (Hocking, A. M., et al. Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol. 17, 1-19 (1998); Lozzo RV. The biology of the small leucine-rich proteoglycans Functional network of interactive proteins. J. Biol. Chem 274, 18843-18846 (1999)). The SLRP family comprises about 17 genes that share structural homologies, such as cysteine residues, leucine rich repeats and at least one glycosaminoglycan side chain. Decorin and biglycan belong to class I, presenting similarities in their amino acid sequence, in the chondroitin or dermatan sulfate side chains and a typical cluster of cysteine residues at the N-terminus that form two disulfide bonds. Fibromodulin and lumican belong to class II, both presenting keratin sulfate and polyactosamines side chains, as well as clusters of tyrosine-sulfate residues at their N-terminal (Schaefer, L., et al. Biological functions of small leucine-rich proteoglycans: from genetics to signal transduction. J. Biol. Chem 283(31), 21305-21309, (2008)). Some SLRPs act as a growth factor reservoir in the extracellular matrix, modulating biological processes, such as cell proliferation and differentiations (Hocking, A. M., et al. Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol. 17, 1-19 (1998); Vogel, K. G., et al. Specific inhibition of type I and type II collagen fibrilogenesis by the small proteoglycan of tendon. Biochem J, 222, 587-597 (1984)). They are capable of inducing signaling cascades through tyrosine kinase, toll-like and TGF-β/BMP receptors (Schaefer, L., et al. Biological functions of small leucine-rich proteoglycans: from genetics to signal transduction. J. Biol. Chem 283(31), 21305-21309, (2008)).
Decorin is a naturally occurring SLRP that is found in the extracellular matrix (EM) of many tissue types in mammals, is a naturally occurring antagonist of scar formation (reviewed by Hocking, A. M., et al. Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol. 17, 1-19 (1998), and is known to inhibit the activity of at least three isoforms of TGF-β (Yamaguchi, Y., et al. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346, 281-284 (1990)). Decorin is also an antagonist of the epidermal growth factor (EGF) receptor tyrosine kinase (Santra, M., et al. Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. J. Biol. Chem. 277, 35671-35681 (2002)) and is known to have both anti-inflammatory and anti-fibrotic properties. After CNS injury, decorin is synthesized by astrocytes in the damaged CNS neuropil (Stichel, C. C., et al. Differential expression of the small chondroitin/dermatan sulfate proteoglycans decorin and biglycan after injury of the adult rat brain. Brain Res 704(2), 263-274 (1995)) and thus may represent an endogenous attempt to down-regulate cytokine activity and promote plasticity of neural circuits within the injured mammalian CNS.
In many cases where neurological function has been lost, such as in a spinal cord injury, there are currently no FDA (United States Food and Drug Administration) approved interventions to reverse the damage and to restore neurological function. Most treatments focus on preventing further injury. Accordingly, there remains a need in the art for novel therapies that promote robust levels of neurological functional recovery when administered to patients suffering from neurological conditions, including CNS injuries and/or diseases.